Epilepsy is the 4th most common neurological disorder, with 1 in 26 people developing epilepsy (the occurrence of more than one unprovoked seizure) at some point in their lifetime. Unfortunately, 30-40% of all patients have intractable (medication-resistant) epilepsy. Thus, new anti-epileptic drugs (AEDs) that target alternative mechanisms of action are needed. The long-term goal of Neuroene Therapeutics is to develop a new non-toxic therapeutic agent for patients with intractable seizures, and for patients who currently have unacceptable adverse effects from their current AED medication. The goal of this STTR is to examine the feasibility of a new class of AEDs by optimizing its serum half-life, bioavailability, and anticonvulsant activity. A small targeted screen using a zebrafish model of epilepsy identified one hit, with a central moiety based on Vitamin K (VK), a natural compound. Additional VK analogs were synthesized. The lead candidate, Alkyne-VK, (1) reduced seizures in zebrafish at concentrations 200-fold less than valproic acid (a common AED), (2) was effective in multiple mouse models of epilepsy, (3) was non-toxic when tested acutely or injected IP daily for three weeks at 100 mg/kg, (4) penetrates mouse brain rapidly within 15 min and (5) has inherent, highly potent neuroprotective properties, due to its role in maintaining energy homeostasis. There are currently no AEDs that target energetics, despite this being a major contributing factor for epilepsy. Having a low therapeutic dose compared to current AEDs on the market means this novel therapy is likely to have fewer side effects. The greatest barrier for this to be a feasible treatment in humans is its short serum half-life (~1 hr). The hypothesis of this Phase I study is that a lead Alkyne-VK analog will be achieved through synergistic chemical modification and rapid in vitro and in vivo characterization, which will be defined as a new feasible AED. Aim 1. Design and synthesize 30-50 Alkyne-VK analogs and confirm neuroprotection in vitro and efficacy in vivo in a zebrafish model of epilepsy. Aim 2: Define the active VK candidate that has excellent brain penetration and retention in mice. At the end of this study, an Alkyne-VK analog candidate with acceptable serum half-life (>6 hr) retaining its anti-epileptic activity will be deemed feasible as a new generation AED. In Phase II studies the lead candidate will be evaluated for its anti-seizure efficacy in multiple mouse models of epilepsy, and undergo full pre-clinical PK/PD, ADME, and full toxicology evaluation leading to a pre-IND filing and meeting with the FDA. As 30-40% of patients do not have good control of their seizures, this represents a population of 4 million in the US, not including patients with adverse effects related to their current medication. We expect the market value to be at least $700 million if the therapy is approved for clinical use, based on a conservative estimation of the AED market at $3.7 billion (20% of the market share). After Phase II, a pre-IND candidate will be identified and partnerships with Pharma/Biotech will be sought in collabration with the Foundation of Research Development at the Medical University of South Carolina, to take the therapeutic agent into human clinical trials.